(4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-bis-naphthalen-2-ylmethyl-[1,3]diazepan-2-one | 153244-86-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-bis-naphthalen-2-ylmethyl-[1,3]diazepan-2-one
• 英文别名: 2H-1,3-Diazepin-2-one, hexahydro-5,6-dihydroxy-1,3-bis(2-naphthalenylmethyl)-4,7-bis(phenylmethyl)-, (4R,5S,6S,7R)-；(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(naphthalen-2-ylmethyl)-1,3-diazepan-2-one
• CAS: 153244-86-1
• 化学式: C₄₁H₃₈N₂O₃
• 分子量: 606.764
• InChiKey: VUYPJDFAKYXJEV-WESAGZJESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  64
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-bis-naphthalen-2-ylmethyl-[1,3]diazepan-2-one 在 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 1.17h， 生成 (4S,5S,6R)-tetrahydro-1,3-bis-<2-naphthylmethyl>-5-hydroxy-4-(1S-bromo-2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone
  参考文献：
  名称：

  Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors

  摘要：

  We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.

  DOI：

  10.1021/jo980533e
• 作为产物：
  描述：

  (4R,5S,6S,7R)-hexahydro-5,6-bis[2-(trimethylsilyl)ethoxymethoxy]-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one 在 盐酸 、 sodium hydride 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 2.5h， 生成 (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-bis-naphthalen-2-ylmethyl-[1,3]diazepan-2-one
  参考文献：
  名称：

  环状HIV蛋白酶抑制剂：合成，构象分析，P2 / P2'的结构活性关系和环状脲的分子识别。

  摘要：

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其

  DOI：

  10.1021/jm9602571

文献信息

• Cyclic HIV Protease Inhibitors:  Synthesis, Conformational Analysis, P2/P2‘ Structure−Activity Relationship, and Molecular Recognition of Cyclic Ureas
  作者：Patrick Y. S. Lam、Yu Ru、Prabhakar K. Jadhav、Paul E. Aldrich、George V. DeLucca、Charles J. Eyermann、Chong-Hwan Chang、George Emmett、Edward R. Holler、Wayne F. Daneker、Liangzhu Li、Pat N. Confalone、Robert J. McHugh、Qi Han、Renhua Li、Jay A. Markwalder、Steven P. Seitz、Thomas R. Sharpe、Lee T. Bacheler、Marlene M. Rayner、Ronald M. Klabe、Linyee Shum、Dean L. Winslow、David M. Kornhauser、David A. Jackson、Susan Erickson-Viitanen、C. Nicholas Hodge

  DOI：10.1021/jm9602571

  日期：1996.1.1

  X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其
• Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors
  作者：George V. De Lucca

  DOI：10.1021/jo980533e

  日期：1998.7.1

  We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.
• Calculated and Experimental Low-Energy Conformations of Cyclic Urea HIV Protease Inhibitors
  作者：C. Nicholas Hodge、Patrick Y. S. Lam、Charles J. Eyermann、Prabhakar K. Jadhav、Y. Ru、Christina H. Fernandez、George V. De Lucca、Chong-Hwan Chang、Robert F. Kaltenbach、Edward R. Holler、Francis Woerner、Wayne F. Daneker、George Emmett、Joseph C. Calabrese、Paul E. Aldrich

  DOI：10.1021/ja972357h

  日期：1998.5.1

  limited number of studies of complex organics that compare calculated and experimentally observed conformations. To assess our ability to predict a priori favored conformations of cyclic HIV protease (HIV-1 PR) inhibitors, conformational minima for nine 4,7-bis(phen...

  影响柔性配体对受体亲和力的一个重要因素是获得结合构象所需的内部应变能。对于大多数生物学感兴趣的系统，计算完全平衡的结合和游离配体和受体构象的集合在计算上是不可能的；因此，将新结构作为给定受体的潜在高亲和力配体的定性评估可以受益于考虑配体的结合和未结合（通常是水性）低能几何形状以及它们的内能差异。尽管可以使用许多计算生成和评估小分子构象偏好的技术，比较计算和实验观察到的构象的复杂有机物研究数量有限。为了评估我们预测循环 HIV 蛋白酶 (HIV-1 PR) 抑制剂的先验偏好构象的能力，九个 4,7-bis(phen...
• Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors
  作者：George V. De Lucca、Jing Liang、Indawati De Lucca

  DOI：10.1021/jm9803626

  日期：1999.1.1

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.